Scleroderma or systemic sclerosis (SSc) is a rare (2-25 cases per 100,000 people) and often fatal human disease believed to have an autoimmune basis and to result from multigenic inheritance and possibly environmental triggers. Besides major histocompatibility complex (MHC) class II alleles, one or more non-HC genes also are believed to be involved in disease susceptibility. Identification of these genes is essential for understanding the pathogenesis of SSc and developing effective treatment or prevention strategies. Genetic linkage studies cannot be applied to SSc because of the rarity of multiplex families. Recent studies of Choctaw Indians living in Oklahoma, but not those in Mississippi, have demonstrated a high prevalence of SSc (469 per 100,000 in full-blooded individuals which shows a strong association with an Amerindian HLA haplotype. Moreover, genealogical studies suggest that European founders may have introduced additional, non-MHC susceptibility genes into this population approximately 10 generations ago. Therefore, this proposal aims to map the susceptibility genes for SSc in the Choctaw using existing high resolution linkage maps consisting of highly polymorphic microsatellite or short tandem repeat polymorphism (STRP) markers which cover >95% of the human genome. STRP markers will first be applied to several candidate genetic regions and then used to scan the entire Choctaw genome at 1OcM distances. Because of evidence for a recent founder effect a previously successful method for identifying disease genes (without need of DNA identical by descent (IBD), (or, linkage disequilibrium or LD) in affected individuals. By studying the Choctaw SSc cases, relatives and controls, either recessive or dominant disease genes lying within 10-20 cM of the marker loci should be identifiable, and then more closely spaced STRP's can further localize the genes. Once susceptibility loci for SSc are identified in the Choctaw, these will be tested in other SSc patients of different ethnic backgrounds, as well as in other autoimmune disease patients and families.